The existence of soluble forms of different cytokine receptors in the biological fluids of mice and humans has suggested that soluble cytokine receptors (sCR) may be important regulatory elements controlling cytokine activity in vivo. The normal physiologic roles of sCR, however, have not been directly investigated and remain a matter of speculation. The long term goals of this project are to determine the role that endogenous forms of soluble interleukin-4 receptors (sIL-4R) play in the regulation of the immune system and to investigate possible applications for sIL-4R as "markers" of immune function and/or activation. The working hypothesis is that endogenous sIL-4R are induced in response to IL-4 secretion and are involved in the regulation of its activity in vivo., through competition with membrane IL-4R indicates that sIL-4R probably have an antagonistic effect on IL-4 activity, particularly at high concentrations, potential effects of sIL-4R on delaying the clearance and inactivation f IL-4 in vivo, may also provide a "carrier effect" for IL-4 in some situations. The specific aims of this proposal are: 1) To characterize the mechanisms involved in the regulation of the production of endogenous sIL-4R and to determine the relationship between sIL-4R secretion and mIL-4R synthesis. This section will investigate the contribution of receptor shedding to the generation of sIL-4R and study the types of cells responsible for sIL-4R secretion and the effects of cellular activation, IL-4 and other cytokines. These studies will be carried out at both the mRNA and protein levels. 2) To determine the role of immune responses and activation of different CD4+T cell subsets (i.e. Th1, Th2) on the production of sIL-4R in vivo. 3) To define the effect of sIL-4R on the pharmacokinetics (half-life, clearance, and tissue distribution) of IL-4 in vivo, using clearance studies in mice injected with radiolabeled IL-4 in the presence or absence of sIL-4R) To determine the role of endogenous sIL-4R on the activity of IL-4 in vivo, by studying the effect of removal/inactivation of sIL-4R through administration of a monoclonal antibody directed against sIL-4R, but not mIL-4R, but not mIL-4R. The significance of these studies is threefold. First, they should help us understand the role of endogenous sIL-4R in the regulation of Il-4 activity in vivo and in immune responses, in general. Second, they should provide information on the association of sIL-4R secretion with the activation of different CD4+T cell subsets and the potential use of measurements of serum levels of sIL-4R as "markers" of such activation. Third, they should provide information on how Il-4 activity in vivo can be modified by the therapeutic use or targeting of sIL-4R. Finally, this investigation should also contribute to our understanding of role of other sCR in the immune system.